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Methods for treating GI syndrome and graft versus host disease

a technology of graft and host disease, which is applied in the field of methods for treating and preventing gi syndrome and graft versus host disease, can solve the problems of increasing the incidence of gvhd, limiting the effective use of this therapy for cancer treatment, and patients susceptible to neoplastic relapse or infection

Active Publication Date: 2013-10-22
BOARD OF RGT THE UNIV OF TEXAS SYST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes the use of ceramide-rich platforms to treat T cell-mediated autoimmune syndromes in vivo. The results show that ceramide is required for T cell-induced apoptosis and that blocking ASMase-generated ceramide can protect against liver damage in a mouse model of acute T cell-mediated liver disease. The patent also describes the use of anti-ceramide antibodies and small interfering RNA to inhibit expression of ASMase and Bax, which are involved in the pathology of graft-versus-host disease, inflammation, and autoimmune diseases. The patent also discusses the use of sustained-release preparations of the therapeutic agents. Overall, the patent provides a technical solution for treating and preventing diseases associated with T cell-mediated inflammation and autoimmunity.

Problems solved by technology

Radiation remains one of the most effective treatments for a wide variety of malignant cells; however healthy cells of the bone marrow, hair follicle, epidermis and gastrointestinal tract are extremely sensitive to radiation-induced cell death, limiting the effective use of this therapy for the treatment of cancer.
The conditioning regimen required prior to transplantation, designed to ablate or suppress the patient's immune system, renders the patient susceptible to neoplastic relapse or infection.
Recent use of unrelated and HLA non-identical donors has unfortunately increased the incidence of GvHD.
While removal of T cells from the donor marrow graft ameliorates GvHD, this strategy increases graft failure rates and markedly diminishes the therapeutically-beneficial graft-versus-tumor effect.
As such, overall survival does not improve.
Further, despite strong pre-clinical data, attempts to improve GvHD outcomes by diminishing inflammatory cytokine action by adding TNF antagonists to corticosteroids, the standard of care for acute GvHD, has provided limited therapeutic benefit.

Method used

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  • Methods for treating GI syndrome and graft versus host disease
  • Methods for treating GI syndrome and graft versus host disease
  • Methods for treating GI syndrome and graft versus host disease

Examples

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example 1

Materials & Methods

Cell Culture and Stimulation

[0155]Wild-type (clone E6-1), caspase 8− / − (clone 19.2) and FADD− / − (clone 12.1) Jurkat T lymphocytes were obtained from ATCC (Rockville, Md.). Cells were grown in a 5% CO2 incubator at 37° C. in RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum and 10 mM Hepes (pH 7.4), 2 mM L-glutamine, 1 mM sodium pyruvate, 100 μM nonessential amino acids, 100 units / ml penicillin, and 100 μg / ml streptomycin. Prior to stimulation with UV-C or anti-Fas, cells were resuspended in fresh medium and allowed to acclimate for 4 hours. Jurkat cells were then treated with 50 ng / ml anti-FasCH-11 activating antibody (Upstate Biotechnology, Lake Placid N.Y.) or 50 Joules / m2 UV-C using an FB-UVXL-1000 Crosslinker (Fisher Biotech, Pittsburgh Pa.), unless otherwise indicated. For platform studies, Jurkat cells were incubated with CH-11 at 4° C. for 20 min to insure uniform receptor engagement, and warmed to 37° C. to initiate stimulation.

[01...

example 2

Role of Asmase in GVHD

[0179]Small intestine, liver and skin were harvested from asmase+ / + and asmase− / − recipients 21 days following transplantation of BM with or without 3×106 T cells. Hematoxylin & Eosin stained liver sections revealed hepatic GvHD, characterized by lymphocyte infiltration (FIG. 22A, arrows), portal tract inflammation, endotheliitis (FIG. 22A, right panels) and loss of hepatic architecture was less prominent in asmase− / − compared to asmase+ / + recipients. Similarly, intestinal GvHD, including villus blunting, lamina propria inflammation, crypt stem cell loss and destruction and mucosal atrophy were less prominent in asmase− / − recipients (FIG. 22B, arrows indicate apoptotic cells). Semiquantitative histopathologic analyses revealed that asmase+ / + recipients of allogeneic bone marrow and T cells scored significantly higher than littermates receiving only BM in liver (Table 1, 15.7±1.5 vs. 8.3±2.7, p+ / + littermates).

[0180]GvHD-associated organ injury is associated wit...

example 3

ASMase Deficiency Protects Against Inflammation

[0183]We next conducted experiments showing that host ASMase inactivation attenuates Th1 / Th2 cytokine profile and CD8+ T cell proliferation in acute GvHD. Initial CTL-mediated tissue damage propagates a feed-forward response requiring CD4+ Th1 cytokine secretion and consequent alloreactive CD8+ clonal expansion for acute GvHD to proceed, followed by inflammatory cytokine storm. To assess the impact of ASMase on serum cytokine levels during GvHD, serum Th1 cytokines IL-2 And IFN-γ and Th2 cytokines IL-1β and TNF-α were quantified 7 and 14 days following transplantation of LP BM with or without splenic T cells. In the minor mismatched model, addition of T cells to the allograft increased IL-2 and IFN-γ from 15.7±4.1 to 30.3±2.8 and 3.7±1.0 to 109.9±18.9 pg / ml serum, respectively (p+ / + hosts) and IL-1β and TNF-α to 2.9±1.2 and 17.3±3.0 pg / ml serum, respectively, (p+ / + hosts and not significant) on day 7 (Table 3). Attenuation of serum cyto...

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Abstract

We have discovered that administering anti-ceramide antibody treats and prevents an array of diseases mediated by cytolytic T lymphocyte (CTLs)-induced killing and by damage to endothelial microvasculture, including radiation-induced GI syndrome, Graft vs. Host diseases, inflammatory diseases and autoimmune diseases. We have also discovered new anti-ceramide monoclonal antibodies, that have therapeutic use preferably in humanized form to treat or prevent these diseases.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a national phase application of PCT Application No. PCT / US2008 / 062789, filed on May 6, 2008, and claims priority to Provisional Appln. 60 / 916,298 filed May 6, 2007, the entire contents of which are hereby incorporated by reference as if fully set forth herein, under 35 U.S.C. §119(e).STATEMENT OF GOVERNMENTAL INTEREST[0002]This invention was made with Government support under National Institutes of Health Grants CA85704. The Government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The invention is in the field of methods for treating and preventing GI Syndrome and Graft Versus Host Disease.[0005]2. Description of the Related Art[0006]Radiation remains one of the most effective treatments for a wide variety of malignant cells; however healthy cells of the bone marrow, hair follicle, epidermis and gastrointestinal tract are extremely sensitive to radiation-indu...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K39/395
CPCC07K16/28A61K2039/505C07K16/40C07K16/44A61K31/55A61P1/00A61P1/04A61P29/00A61P35/00A61P35/02A61P37/02A61P37/06A61P39/00
Inventor ROTOLO, JIMMY ANDREWKOLESNICK, RICHARDPASQUALINI, RENATAARAP, WADIH
Owner BOARD OF RGT THE UNIV OF TEXAS SYST
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